ABSTRACT A substantial number of critically ill patients experience persistent organ failure leading to chronic critical illness (CCI). The majority of these patients die within a year, and many survivors must cope with long-term physical and cognitive limitations that are often severe. Survival with severe physical and cognitive dysfunction is a significant clinical, emotional, and economic burden in this population, but little is known about which patients are at highest risk for physical and cognitive dysfunction. Moreover, although long-term mortality in CCI can be reliably estimated with a validated mortality prediction model, there is currently no validated method to predict long-term functional disability for purposes of shared decision making and resource planning. In order to address these gaps in knowledge, we will conduct the first multicenter prospective cohort study that measures risk factors for long-term physical and cognitive dysfunction in CCI. Using these risk factors, we will construct a useful and innovative multi-outcome prognostic model to facilitate shared decision making and resource planning. Specific aims for the project are as follows: 1. Identify risk factors for long-term physical and cognitive dysfunction for patients with CCI. 2. Develop and validate an innovative multi-dimensional clinical prediction model to predict the combined outcome of long-term survival and physical and cognitive function in patients with CCI. We will accomplish these aims by prospectively enrolling 800 patients from 5 diverse medical centers who have required 7 days of mechanical ventilation after acute illness or injury, and we will follow them for up to 1 year. On day 7 of mechanical ventilation we will collect data on lung function, neuromuscular weakness, acute brain dysfunction, and other selected clinically available biomarkers. Premorbid functional decline including validated frailty indices, and social and environmental variables will be obtained from medical records and family interviews. For the first aim these variables will be evaluated as independent risk factors for severe physical and cognitive dysfunction at one-year, focusing first on clinical variables and then on social and economic factors. For the second aim we will construct and validate a single multi-outcome model using a single set of variables to predict survival with severe physical disability, survival with severe cognitive disability, survival with physical and cognitive disability, survival with normal function, and death. This project is important because it will directly provide new tools for patients and clinicians to understand CCI, informing bedside decision making and future medical and resource interventions for this extremely high-risk patient group.